Kalirin Dbl-Homology Guanine Nucleotide Exchange Factor 1 Domain Initiates New Axon Outgrowths via RhoG-Mediated Mechanisms

Authors

Victor May, University of Vermont
Martin R. Schiller, University of Nevada, Las VegasFollow
Betty A. Eipper, University of Connecticut Health CenterFollow
Richard E. Mains, University of Connecticut Health CenterFollow

Document Type

Article

Publication Date

8-15-2002

Publication Title

The Journal of Neuroscience

Volume

22

Issue

16

First page number:

6980

Last page number:

6990

Abstract

The large multidomain Kalirin and Trio proteins containing dual Rho GTPase guanine nucleotide exchange factor (GEF) domains have been implicated in the regulation of neuronal fiber extension and pathfinding during evelopment. In mammals, Kalirin is expressed predominantly in the nervous system, whereas Trio, broadly expressed throughout the body, is expressed at a lower level in the nervous system. To evaluate the role of Kalirin in fiber initiation and outgrowth, we microinjected cultured sympathetic neurons with vectors encoding Kalirin or with Kalirin antisense oligonucleotides, and we assessed neuronal fiber growth in a serum-free, satellite cell-free environment. Kalirin antisense oligonucleotides blocked the continued extension of preexisting axons. Kalirin overexpression induced the prolific sprouting of new axonal fibers that grew at the normal rate; the activity of Kalirin was entirely dependent on the activity of the first GEF domain. KalGEF1-induced sprouting of new fibers from lamellipodial structures was accompanied by extensive actin cytoskeleton reorganization. The kalGEF1 phenotype was mimicked by constitutively active RhoG and was blocked by RhoG inhibitors. Constitutively active Rac1, RhoA, and Cdc42 were unable to initiate new axons, whereas dominant-negative Rac1, RhoA, and Cdc42 failed to block axon sprouting. Thus Kalirin, acting via RhoG in a novel manner, plays a central role in establishing the morphological phenotypic diversity that is essential to the connectivity of the developing nervous system.

Keywords

Dbl-Homology; Kalirin; G proteins; Guanine Nucleotide Exchange Factor; Rho Gtpases; Nervous system; Neuronal Fiber Outgrowth; Trio

Disciplines

Anatomy | Biochemistry, Biophysics, and Structural Biology | Life Sciences | Neurosciences | Pharmacology, Toxicology and Environmental Health

Language

English

Repository Citation

May, V., Schiller, M. R., Eipper, B. A., Mains, R. E. (2002). Kalirin Dbl-Homology Guanine Nucleotide Exchange Factor 1 Domain Initiates New Axon Outgrowths via RhoG-Mediated Mechanisms. The Journal of Neuroscience, 22(16), 6980-6990.
https://digitalscholarship.unlv.edu/sls_fac_articles/170